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Title
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Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents
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Author
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Abstract
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| Trypanosoma cruzi is the causative pathogen of Chagas disease and the main culprit for cardiac-related mortality in Latin-America triggered by an infective agent. Uncapable of synthesizing purines de novo, this parasite depends on acquisition and processing of host-derived purines, making purine (nucleoside) analogues a potential source of antitrypanosomal agents. In this respect, hitherto 7-deazaadenosine (tubercidin) analogues attracted most attention. Here, we investigated analogues with an additional nitrogen (N1) removed. Structure-activity relationship investigation showed that C7 modification afforded analogues with potent antitrypanosomal activity. Halogens and small, linear carbon-based substituents were preferred. Compound 11 proved most potent in vitro, showed full suppression of parasitemia in a mouse model of acute infection and elicited 100 % animal survival after oral dosing at 25 mg/kg b.i.d. for five and fifteen days. Cyclophosphamide-induced immunosuppression led to recrudescence. Washout experiments demonstrated a lack of complete clearance of infected cell cultures, potentially explaining the in vivo results. |
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Language
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English
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Source (journal)
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Journal of medicinal chemistry. - Washington, D.C., 1963, currens
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Publication
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Washington, D.C.
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2019
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ISSN
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0022-2623
[print]
1520-4804
[online]
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DOI
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10.1021/ACS.JMEDCHEM.9B01275
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Volume/pages
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62
:19
(2019)
, p. 8847-8865
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ISI
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000490355000013
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Pubmed ID
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31495177
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Full text (Publisher's DOI)
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Full text (open access)
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